Why Q3D? Elemental Impurities: Is Your Company Prepared for ICH Q3D

Transcription

1 Elemental Impurities: Is Your Company Prepared for ICH Q3D J. Skutnik-Wilkinson VP NSF Health Sciences Pharma Biotech Q3D EWG member Quality Session 2 May 13, 2014 Why Q3D? Pharmacopoeias going in different directions Industry concern for having different expectations globally (eg Metal Catalysts Guide EU) No harmonised guidance A need for a valid science and risk based approach Recognition that this is more complicated that Residual Solvents 2014 NSF Intl. 2 1

2 Topic Adopted 2008 EWG developed drafts Step 2b Sign off June 2013 Public Consultation: Through 31 Dec 2013 Feb 2014 June 2014 Review comments received & Revise Guideline as needed Goal Sign off Step 4 June NSF Intl 3 Objectives of Guideline Deliverables Harmonized, safety based limits for elemental impurities, especially those with highest toxicological concern. Selection of elements to control Methodology for establishing safety based limits Permitted daily exposures for specific elements Appropriate risk based approach to ensure control for elements likely to be present in drug products and ingredients. A harmonized guideline to ensure globally consistent control of elemental impurities 2014 NSF Intl. 4 2

3 Key Points Establishes Permitted Daily Exposure (PDEs) for Finished Drug Products Oral / Parenteral / Inhalation Routes of Administration PDEs based on key toxicology studies and relevant data PDEs apply ONLY to finished dosage forms NOT to individual components HOWEVER: need to understand the contributions from excipients, API, packaging components in order to comply with PDEs Applies to new drug products & new products (containing existing APIs) No consistent approach to how this will be implemented for existing products 2014 NSF Intl. 5 Principles of Safety Assessment Longest Duration Animal study (generally used) Most Relevant Animal Study Likely Oxidation State of the element in the drug product Route of Administration Human Exposure & Safety Data Selection of Relevant End Points or designations 2014 NSF Intl. 6 3

4 Justification for Higher Levels Less than Daily Dosing Short term exposure Specific Indications Toothpaste Talcum powder Headache tablets 7 day course of antibiotics 10 day course of Prednisone Medications for a life threatening medical need Un met medical needs Rare Diseases 2014 NSF Intl NSF Intl 8 4

5 Classification CLASS Elemental Impurities Include in Risk Assessment 1 As, Pb, Cd, HG YES 2A V, Mo, Se, Co YES 2B Ag, Au, Tl, Pd, Pt, Ir, Os, Rh, Ru YES: ONLY if intentionally added 3 Sb, Ba, Li, Cr, Cu, Sn, Ni Dependent on Route of Administration 4 B, Fe, Zn, K, Ca, Na, Mn, Mg, W, Al No 2014 NSF Intl. 9 Data Collection Near Term: some testing will be needed to determine levels currently present For elements that are primarily catalysts can simply rule those out through prior knowledge when not used Most complicated aspect is for materials with naturally sourced excipients Guideline does not mandate nor expect screening for all metals Longer Term: Testing is not the default Elements not likely to be present document Elements <30% of PDE no further controls (aside from re assessing when there are changes to suppliers/formulation/process etc) Special considerations may be needed for naturally sourced excipients 2014 NSF Intl. 10 5

6 Challenges Methodology & pharmacopoeial implementation Bioavailability Absorption Additional Dosage Forms No defined Daily Dose Intermittent Dosing Existing products 2014 NSF Intl. 11 Defining a Strategy Prior Knowledge Risk Assessment What do we know already? What can we find out? Determine possibility, probability Data Collection & Analysis Testing Strategy Method development Validation How to handle results What to test for, when and by whom? 2014 NSF Intl. 12 6

7 Prior Knowledge Product Max Daily Dose Administration Route Indication Dosing Regime Types of excipients Levels of elements present (suppliers may have data based on other industries they supply) Process Catalysts? Equipment? Steps within process that may contribute to levels of elemental impurities Analytical Elemental impurities already known and controlled Pharmacopoeial specifications 2014 NSF Intl. 13 Identification of Potential Elemental Impurities From intentionally added catalysts or reagents Naturally sourced excipients / materials Class 1 = always include in risk assessment Derived from Manufacturing Equipment Leached from Container Closure Systems 2014 NSF Intl. 14 7

8 Data Collection Screening: Consider high risk products Those with high levels of naturally sourced excipients or multiple naturally sourced excipients Supplier Information: engage in discussions with suppliers regarding any information they may have (do not just send out questionnaires) Other: Literature searches Consider working with trade & professional organizations to create data repository FDA study data 2014 NSF Intl 15 Data Analysis <30% of PDE: Consider no further testing except when changes occur (supplier changes/ process changes >30% but <100%: Consider what you know about what is contributing to the levels and develop a strategy for control (remember CONTROL does not always = eliminate) > PDE Dialogue with Regulatory Agencies (situation is unlikely based on the volume of data generated by FDA and others to date) 2014 NSF Intl. 16 8

9 Testing Strategy Special Considerations Products with high levels of naturally sourced materials or multiple naturally source materials Special Considerations Do NOT have to screen for all Elemental impurities Knowledge that elemental impurities levels are highly variable in an ingredient A good risk assessment (science and knowledge based) may suffice in lieu of any testing Short term strategy may be different from your longer term strategy Do not expect to see elemental impurity results on Suppliers COAs 2014 NSF Intl. 17 Implementation Decide on a company wide strategy (short term and long term) Engage in Dialogue with suppliers Consider industrywide collaborations Focus on highest risks Engage in Discussions with Regulators when there are issues Consider strategy for additional dosage forms 2014 NSF Intl. 18 9

10 Remaining Challenges Additional Dosage Forms Implementation for existing products Bioavailability 2014 NSF Intl. 19 USP Considerations Delayed implementation As promised to EWG 01 December 2015 Alignment USPs limit diverge from ICH Q3D stage 2b draft Discussions underway Industry should continue to comment to USP regarding alignment Issue Resolution USP has committed to work with Industry and the FDA to resolve and monograph issues Methods <231> will be omitted from 01 Dec 2015 Replaced with Chapter <232> 2014 NSF Intl

11 Closing Thoughts The concepts of Risk Assessment, Risk Management and Risk Mitigation are infused throughout Testing is not the default Careful consideration of possible sources of metals is inherent Company s cannot and must not insist that their excipient/raw material suppliers meet extremely low specifications or eliminate metals In majority of cases this is not even possible due to the nature of the materials 2014 NSF Intl. 21 Questions? 2014 NSF Intl

12 Thank You NSF International 23 12